Rimonabant-Based Compounds Bearing Hydrophobic Amino Acid Derivatives as Cannabinoid Receptor Subtype 1 Ligands.

In this study, 1 H -pyrazole-3-carboxylic acids related to the cannabinoid type 1 (CB1) receptor antagonist rimonabant were amidated with valine or tert -leucine, and the resulting acids were further diversified as methyl esters, amides, and N -methyl amides. In vitro receptor binding and functional assays demonstrated a wide series of activities related to the CB1 receptors (CB1Rs). Compound 34 showed a high CB1R binding affinity ( K i = 6.9 nM) and agonist activity (EC 50 = 46 nM; E max = 135%). Radioligand binding and [ 35 S]GTPγS binding assays also demonstrated its selectivity and specificity to CB1Rs. Moreover, in vivo experiments revealed that 34 was slightly more effective than the CB1 agonist WIN55,212-2 in the early phase of the formalin test, indicating a short duration of the analgesic effect. Interestingly, in a mouse model of zymosan-induced hindlimb edema, 34 was able to maintain the percentage of paw volume below 75% for 24 h following subcutaneous injection. After intraperitoneal administration, 34 increased the food intake of mice, suggesting potential activity on CB1Rs.